September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Temporal Expression of Cone-specific Recombinant Adeno-associated Viruses in Multiple Species Exhibiting Various Cone Levels as Potential Models to Treat Cone-Associated Disorders
Author Affiliations & Notes
  • Alex Bauer
    Avalanche Biotechnologies, San Carlos, California, United States
  • Steven Tobia
    Avalanche Biotechnologies, San Carlos, California, United States
  • Kathryn W Woodburn
    Avalanche Biotechnologies, San Carlos, California, United States
  • Ming Ni
    Avalanche Biotechnologies, San Carlos, California, United States
  • Footnotes
    Commercial Relationships   Alex Bauer, None; Steven Tobia, None; Kathryn Woodburn, None; Ming Ni, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 781. doi:
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      Alex Bauer, Steven Tobia, Kathryn W Woodburn, Ming Ni; Temporal Expression of Cone-specific Recombinant Adeno-associated Viruses in Multiple Species Exhibiting Various Cone Levels as Potential Models to Treat Cone-Associated Disorders. Invest. Ophthalmol. Vis. Sci. 2016;57(12):781.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Innovative treatments are needed for cone photoreceptor-associated disorders. AAV-mediated gene delivery of a therapeutic gene to cone photoreceptors may have the potential to rescue cone viability and function in cone-mediated macular dystrophies. To model transduction and safety of AAV gene therapy, cone-specific promoter (MNTC and PR2.1) driven green fluorescent protein (GFP) transgene expression was evaluated in preclinical species with varying amounts of cone cells, including mouse (3%), rat (1%), gerbil (13%), and ground squirrel (97%) and results compared against a ubiquitous promoter (CMV).

Methods : Intraocular gene expression of AAV2-7m8 vector variants driven by the cone specific (PR2.1 and MNTC) and ubiquitous (CMV) promoters was evaluated for up to 42 weeks. The vectors were intravitreally administered bilaterally to mice (C57BL/6, 1 µL), rats (Brown Norway, 5 µL), gerbils (Mongolian, 5 µL), and squirrels (ground, 10 µL). GFP expression was monitored using a fundus camera equipped with a GFP filter and strength of transgene expression was scored from 0 (no expression) to 4 (maximum expression) at weeks 2 and 4, then every 4 to 6 weeks up to 42 weeks. Eye examinations, clinical observations, and body weight analyses were performed.

Results : Intravitreal delivery of the vectors was well tolerated. GFP expression kinetics varied with the vectors variants and species. The cone promoters exhibited robust and sustained expression in squirrel and gerbil retina, compared to little or no GFP expression in rat and mouse retina. Initiation of transgene expression was observed earlier in squirrel retina compared to gerbil retina that showed higher expression at the visual streak, which specifically has higher cone density in that region. Furthermore, anatomic location of GFP expression from MNTC and PR2.1 correlated with cone abundance and location.

Conclusions : Cone-specific promoters like MNTC or PR2.1 may be optimal for use to obtain robust and sustained transgene expression specifically in cone photoreceptors. Also, gerbils and squirrels may be valuable model animals to use for evaluating pharmacology and safety of new agents for cone-associated disorders.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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